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WO2003002566A1 - Derives puriniques utilises comme antagonistes du recepteur de l'adenosine a2b - Google Patents

Derives puriniques utilises comme antagonistes du recepteur de l'adenosine a2b Download PDF

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Publication number
WO2003002566A1
WO2003002566A1 PCT/US2002/020631 US0220631W WO03002566A1 WO 2003002566 A1 WO2003002566 A1 WO 2003002566A1 US 0220631 W US0220631 W US 0220631W WO 03002566 A1 WO03002566 A1 WO 03002566A1
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Prior art keywords
optionally substituted
compound
formula
purine
diamine
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PCT/US2002/020631
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English (en)
Inventor
Venkata Palle
Vaibhav Varkhedkar
Jeff A. Zablocki
Dengming Xiao
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Cv Therapeutics, Inc.
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Priority to SI200230236T priority Critical patent/SI1401837T1/sl
Priority to EP02749704A priority patent/EP1401837B1/fr
Priority to DE60206756T priority patent/DE60206756T2/de
Priority to CA2451244A priority patent/CA2451244C/fr
Priority to JP2003508947A priority patent/JP4335000B2/ja
Priority to AT02749704T priority patent/ATE307132T1/de
Priority to KR1020037017083A priority patent/KR100883292B1/ko
Publication of WO2003002566A1 publication Critical patent/WO2003002566A1/fr
Priority to HK04106852A priority patent/HK1064096A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to novel compounds that are A 2B adenosine receptor antagonists, and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunological disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like.
  • the invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
  • Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A ! , A 2a , A 2 , and A 3 , all of which modulate important physiological processes.
  • a ⁇ adenosine receptor agonists modulate the cardiostimulatory effects of catecholamine, thus slowing the heart rate, and also prolong impulse propagation through the AN node.
  • stimulation of A ⁇ receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter.
  • a 2A adenosine receptors modulate coronary vasodilation
  • a 2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A 2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153), and A 3 adenosine receptors modulate cell proliferation processes.
  • Adenosine A 2B receptors are ubiquitous, and regulate multiple biological activities. For example, adenosine binds to A 2B receptors on endothelial cells, thereby stimulating angiogenesis. Adenosine also regulates the growth of smooth muscle cell populations in blood vessels. Adenosine stimulates A 2B receptors on mast cells, thus modulating Type I hypersensitivity reactions. Adenosine also stimulates gastrosecretory activity by ligation with A 2 B in the intestine. Binding of A 2B receptors in the brain leads to the release of IL-6, which provides a protective effect to the cerebrum from ischemia
  • adenosine While many of these biological effects of adenosine are necessary to maintain normal tissue homeostasis, under certain physiological changes it is desirable to curtail its effects. For example, the binding of A 2B receptors stimulates angiogenesis by promoting the growth of endothelial cells. Such activity is necessary in healing wounds, but the hyperproliferation of endothelial cells promotes diabetic retinopathy. Also, an undesirable increase in blood vessels occurs in neoplasia. Accordingly, inhibition of the binding of adensoine to A 2B receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibiting tumor formation. Adenosine also plays a role in vascular disease by causing the apoptosis of smooth muscle cells, leading to atherosclerosis and restenosis.
  • a 2B receptors are found in the colon in the basolateral domains of intestinal epithelial cells, and when acted upon by the appropriate ligand act to increase chloride secretion, thus causing diarrhea, which is a common and potentially fatal complication of infectious diseases such as cholera and typhus.
  • a 2B antagonists can therefore be used to block intestinal chloride secretion, and are thus useful in the treatment of inflammatory gastrointestinal tract disorders, including diarrhea.
  • Insensitivity to insulin exacerbates diabetes and obesity. Insulin sensitivity is decreased by the interaction of adenosine with A 2B receptors. Thus, blocking the adenosine A 2B receptors of individuals with diabetes or obesity would benefit patients with these disorders.
  • adenosine acting at the A 2B receptor is the over- stimulation of cerebral IL-6, a cytokine associated with dementias and Alzheimer's disease. Inhibiting the binding of adenosine to A 2B to receptors would therefore mitigate those neurological disorders that are produced by IL-6.
  • Type I hypersensitivity disorders such as asthma, hay fever, and atopic eczema
  • asthma are stimulated by binding to A 2B -receptors of mast cells. Therefore, blocking these adenosine receptors would provide a therapeutic benefit against such disorders.
  • theophylline is an effective antiasthmatic agent, even though it is a poor adenosine receptor antagonist. However, considerable plasma levels are needed for it to be effective. Additionally, theophylline has substantial side effects, most of which are due to its CNS action, which provide no beneficial effects in asthma, and to the fact that it non-specifically blocks all adenosine receptor subtypes.
  • adenosine treatment such as inhaled adenosine provokes bronchoconstriction in asthmatics, but not in the normal population.
  • This process is known to involve mast cell activation, in that it releases mast cell mediators, including histamine, PGD2- ⁇ -hexosaminidase and tryptase, and because it can be blocked by specific histamine , Hi blockers and chromolyn sodium.
  • mast cell mediators including histamine, PGD2- ⁇ -hexosaminidase and tryptase
  • Hi blockers chromolyn sodium
  • the compounds are potent A 2B antagonists, useful in the treatment of various disease states related to modulation of the A 2B receptor, in particular cancer, asthma and diarrhea.
  • the compounds would be selective for the A 2B receptor, thus avoiding side effects caused by interaction with other adenosine receptors.
  • the invention relates to compounds of Formula I:
  • R 1 is optionally substituted alkyl or a group -Y-Z, in which Y is a covalent bond or optionally substituted alkylene, and Z is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl;
  • R is hydrogen, acyl, optionally substituted alkyl, or a group -Y-Z, in which Y is a covalent bond or optionally substituted alkylene, and Z is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl;
  • R is hydrogen, optionally substituted alkyl or a group -Y-Z , in which Y is a covalent bond or optionally substituted alkylene, and Z 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino, optionally substituted alkenyl or optionally substituted alkynyl, with the proviso that when Y is a covalent bond Z cannot be optionally substituted amino;
  • R 4 and R 6 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 5 is hydrogen, optionally substituted alkyl, halo, CF 3 , nitro, cyano, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted amino, optionally substituted sulfoxide, optionally substituted sulfone, optionally substitute
  • a second aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I and at least one pharmaceutically acceptable excipient.
  • a third aspect of this invention relates to a method of using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be usefully treated with an A 2B receptor antagonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I.
  • diseases include, but are not limited to, inflammatory gastrointestinal tract disorders, including diarrhea, cardiovascular diseases, such as atherosclerosis, neurological disorders such as senile dementia, Alzheimer's disease, and Parkinson's disease, diseases related to unwanted angio genesis, for example diabetic retinopathy and cancer, and asthma.
  • One preferred class includes those compounds of Formula I in which X is -NH-, particularly those in which R 1 is optionally substituted alkyl and R 2 is hydrogen, alkyl or acyl.
  • R is optionally substituted alkyl
  • R is hydrogen
  • R 3 is -Y-Z 1
  • Y is optionally substituted alkylene and Z 1 is optionally substituted aryl
  • R 4 , R 5 and R 6 are hydrogen, halogen, optionally substituted alkyl or optionally substituted alkenyl.
  • R 1 is lower alkyl or 1-3 carbon atoms, particularly ethyl or n-propyl
  • Y is lower alkylene of 1-3 carbon atoms, particularly methylene or ethylene
  • Z is optionally substituted phenyl.
  • R 4 and R 6 are hydrogen or methyl
  • R 5 is hydrogen, optionally substituted phenyl, lower , alkyl, ( or lower alkenyl.
  • Particularly preferred are those in which R 4 , R 5 and R 6 are all hydrogen.
  • Another preferred class are those compounds in which R 2 is acyl.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • substituted alkyl refers to:
  • an alkyl group as defined above having from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO- heteroaryl, -SO 2 -alkyl, SO 2 -ary
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
  • alkyl group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and -NR a -, where R a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl.
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or 3) an alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
  • the term "lower alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms.
  • This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.
  • substituted lower alkyl refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1 to 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1-5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms as defined above.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and- CH(CH3)CH2-) and the like.
  • lower alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 6 carbon atoms.
  • substituted alkylene refers to: (1) an alkylene group as defined above having from 1 to 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
  • an alkylene group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and NR a -, where R a is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or
  • alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above.
  • substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (-CH(NH 2 )CH 2 -), methylaminoethylene (-CH(NHMe)CH 2 -), 2-carboxypropylene isomers(-
  • aralkyl refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.
  • Optionally substituted aralkyl refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group.
  • Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
  • alkoxy refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y is optionally substituted alkylene and Z is; optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein.
  • Preferred alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, 1,2-dimethylbutoxy, and the like.
  • alkylthio refers to the group R-S-, where R is as defined for alkoxy.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl).
  • lower alkenyl refers to alkenyl as defined above having from 2 to 6 carbon atoms.
  • substituted alkenyl refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynyl groups include ethynyl, (-C ⁇ CH), propargyl (or propynyl, -CH 2 C ⁇ CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.
  • substituted alkynyl refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, hetero aryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • aminocarbonyl refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino) .
  • All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or - S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • acylamino refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or-S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • acyloxy refers to the groups -O(O)C-alkyl, -O(O)C-cycloalkyl, -O(O)C- aryl, -O(O)C-heteroaryl, and -O(O)C-heterocyclyl. All substituents maybe optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or - S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • aryl refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -S O-aryl,
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and - S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2;.
  • aryloxy refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above.
  • arylthio refers to the group R-S-, where R is as defined for aryl.
  • amino refers to the group -NH 2 .
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl.
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, > aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and - S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • Carboxyalkyl refers to the groups -C(O)O-alkyl, -C(O)O-cycloalkyl, where alkyl and cycloalkyl may be optionally substituted as defined herein.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example inda ⁇ , and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and-S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • halogen or “halo” refers to fluoro, bromo, chloro, and iodo.
  • acyl denotes a group -C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • heteroaryl refers to an aromatic group (i.e., unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
  • such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, amino
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -
  • heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazole, or benzothienyl).
  • nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, , indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxy- nitrogen containing heteroaryl compounds.
  • heteroaryloxy refers to the group heteroaryl-O-.
  • heterocyclyl refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heter
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and - S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • Heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.
  • thiol refers to the group -SH.
  • substituted alkylthio refers to the group -S-substituted alkyl.
  • heteroarylthiol refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
  • sulfoxide refers to a group -S(O)R, in which R is alkyl, aryl, or heteroaryl.
  • Substituted sulfoxide refers to a group -S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
  • sulfone refers to a group -S(O) 2 R, in which R is alkyl, aryl, or heteroaryl.
  • substituted sulfone refers to a group -S(O) 2 R, in which R is substituted alkyl, substituted aryl, ,or substituted heteroaryl, as defined herein.
  • keto refers to a group -C(O)-.
  • thiocarbonyl refers to a group - C(S)-.
  • carboxy refers to a group -C(O)-OH.
  • compound of Formula I is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, and prodrugs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2 n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. "Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line.
  • therapeutically effective amount refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a , mammal in need of such treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • treatment or “treating” means any treatment of a disease in a mammal, including:
  • the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds of Formula I, and which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkeny
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanplamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like].
  • solvents used in the reactions of the present invention are inert organic solvents.
  • q.s means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
  • the compounds of Formula I may be prepared starting from 2,6-dichloropurine, as shown in Reaction Scheme I.
  • the compound of formula (2) is prepared conventionally from the commercially available compound of formula (1), 2,6-dichloropurine, by reaction with an amine of the formula R NH 2 .
  • R is hydrogen
  • ammonia is reacted under pressure in a protiq solvent, for example methanol, at a temperature of 60-100°C, for about two days.
  • the product of formula (2) is isolated by conventional means, for example removal of the solvent under reduced pressure.
  • the compound of formula (2) is then converted to a compound of formula (3) by alkylation at the 9-position.
  • the compound of formula (2) is reacted with a halide of formula R*X, where R 1 is as defined above, with the proviso that it cannot be aryl, and X is chloro, bromo, or iodo, preferably iodo, in the presence of a base, preferably potassium carbonate, in a suitable solvent, preferably acetone.
  • the reaction is preferably conducted at reflux, for about 18 hours.
  • the product of formula (3) is isolated by conventional means, for example removal of the solvent under reduced pressure and slurrying with water before filtering.
  • the 2-chloro moiety is then displaced from the compound of fo ⁇ nula (3) by reaction with a compound of formula R XH when X is NH, in the presence of a base, or R XM, where X is oxygen or sulfur and M is an alkali metal.
  • the reaction is carried out in an inert protic solvent, preferably n-butanol, at a temperature of about reflux, for about 24-48 hours.
  • an inert protic solvent preferably n-butanol
  • Step 4 - Preparation of Formula (5) The compound of formula (4) is then converted to the 8-bromo derivative of formula
  • the compound of formula (5) is then converted to a compound of Formula I where R 2 is hydrogen by reaction with an optionally substituted pyrazole in the presence of an alkali hydride, preferably sodium hydride.
  • the reaction is carried out in an inert polar solvent, preferably dimethylfonnamide, at about 80°C, for about 18 hours.
  • an inert polar solvent preferably dimethylfonnamide, at about 80°C, for about 18 hours.
  • the product of Formula I where R 2 is hydrogen is isolated by conventional means, for example by removal of the solvent under reduced pressure, partitioning between dichloromethane and water, separation of the organic layer, removal of solvent, followed by chromatography of the residue on silica gel.
  • the compound of Formula I where R >2 is hydrogen is then converted to a compound of Formula I where R 2 is acyl, by reaction with a compound of formula RC(O)Cl, where RC(O)- represents R 2 when R 2 is defined as acyl, in the presence of a tertiary base, preferably triethylamine.
  • the reaction is carried out in an inert solvent, preferably toluene, at about reflux temperature for about 18 hours.
  • the product of Formula I where R 2 is acyl is isolated by conventional means, for example by partitioning the crude reaction mixture between dichloromethane and water, separating the organic layer, removing the solvent under reduced pressure, followed by chromatography of the residue on silica gel, preferably TLC.
  • a preferred method of preparing a compound of formula (3) in which R 1 is -Y-Z, in which Y is a covalent bond and Z is aryl or heteroaryl is to first react the dichloropurine of formula (1) with a optionally substituted aryl-trialkylstannane in the presence of a copper catalyst, for example copper acetate, and a source of fluoride ions, preferably tetrabutylammonium fluoride.
  • a copper catalyst for example copper acetate
  • a source of fluoride ions preferably tetrabutylammonium fluoride
  • the product is a 2,6-dichloro-7-arylpurine, which is then reacted as described in step 1 with an amine of formula R 2 NH 2 to give a compound of formula (3) in which R 1 is optionally substituted aryl.
  • This reaction is utilized to provide, for example, 2-chloro-6-amino-7-(3- carboxamido)phenyl, a compound of formula (3), which is then converted as shown in Reaction Scheme 1 to a compound of Formula I, for example N 2 -[2-(3- fluorophenyl)ethylamino)-8-(pyrazol-l-yl)-9-(3-carboxamidophenyl)-9H-purine-2,6-diamine.
  • reaction is carried out as shown in Reaction Scheme 1 above, Step 5, reacting with an optionally substituted 4-iodopyrazole.
  • the compound of Formula I where R 5 is iodo is isolated as before.
  • the compound of Formula I where R 5 is iodo is then converted to a compound of Formula I where R 5 is optionally substituted phenyl by reaction with an optionally substituted phenylboronic acid.
  • the reaction is carried out in an inert solvent, preferably toluene, in the presence of aqueous sodium carbonate solution and tetrakis(triphenylphosphine)palladium(0), at about reflux temperature for about 24 hours. Excess boronic acid derivative is quenched by addition of hydrogen peroxide.
  • the product of Formula I where R 2 is hydrogen is isolated by conventional means, for example by partitioning the crude reaction mixture between dichloromethane and water, separating the , organic layer, removing the solvent under reduced pressure, followed by chromatography of the residue on silica gel, preferably TLC.
  • the compound of Formula I where R 5 is iodo is converted to a compound of Formula I where R 5 is vinyl by reaction with tributylvinyltin, tetrakis(triphenylphosphine)palladium(0), and copper iodide. This compound is then hydrogenated in the presence of palladium on carbon catalyst, to give a compound of Formula I where R 5 is ethyl.
  • the compound of formula (5) is converted to a compound of formula (6) by reaction with hydrazine hydrate.
  • the reaction is carried out in a protic solvent, preferably ethanol, at about reflux, preferably about 80°C, for about 24 hours.
  • a protic solvent preferably ethanol
  • the product of formula (6) is isolated by conventional means, for example by t partitipning between ether and water, separation of the organic layer, drying the solvent, and removal of solvent under reduced pressure.
  • the compound of Formula (6) is used for the next step without purification.
  • the compound of formula (6) is converted to a compound of Formula I by reaction with an optionally substituted 1,3-propanedione of formula (7).
  • the reaction is carried out in a protic solvent, preferably methanol/acetic mixture, at about reflux, for about 24 hours.
  • a protic solvent preferably methanol/acetic mixture
  • the product of Fonnula I is isolated by conventional means, for example by removal of solvent under reduced pressure, followed by chromatography of the residue on silica gel, preferably TLC.
  • a strong base preferably sodium hydride.
  • the compounds of Formula I are effective in the treatment of conditions that respond to administration of A 2B adenosine receptor antagonists.
  • Such conditions include, but are not limited to, diarrhea, atherosclerosis, restenosis, diabetic retinopathy, cancer, senile dementia, Alzheimer's disease, Parkinson's disease, traumatic brain injury, and Type I hypersensitivity reactions, including asthma, atopic eczema, and hay fever.
  • the compounds of Formula I are usually administered in the form of pharmaceutical compositions.
  • This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • the compounds of Formula I may be administered alone or in combination with other therapeutic agents.
  • Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17 th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3 rd Ed. (G.S. Banker & CT. Rhodes, Eds.). Administration
  • the compounds of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery- inserted cylindrical polymer.
  • One mode for administration is parental, particularly by injection.
  • Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Sterile injectable solutions are prepared by incorporating the compound of Formula I in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the prefened methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral administration is another route for administration of the compounds of Formula I.
  • Administration may be via capsule or enteric coated tablets, or the like.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, in can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated , reser ⁇ oirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345.
  • Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the compositions are preferably formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
  • the compounds of Formula I are effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • each dosage unit contains from 10 mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of a compound of Formula I, more preferably about 50-200 mg. It will be understood, however, that the amount of the compound of Formula I actually administered will be detennined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • the compound of formula (2) (8.9g, 0.053 mole), potassium carbonate (18.31g, 0.133 mole), and ethyl iodide (6.36mL, 0.08 moles) were combined in lOOmL of acetone and stirred at reflux for 18 hours. The mixture was cooled and the solvent evaporated. To the residue was added water (250 mL), and the mixture was filtered to give a compound of formula (3) where R 1 is ethyl (2-chloro-9-ethylpurine-6-ylamine), as a buff colored solid.
  • R 1 is ethyl (2-chloro-9-ethylpurine-6-ylamine) (0.9g, 4.55mmoles), triethylamine (1.27mL, 9mmoles), and benzylamine(lmL, 9 mmoles) were mixed in 1-butanol (lOmL) and stirred at reflux for 24 hours. Another ImL of benzylamine was added and the refluxing continued for another 24 hours.
  • N 2 (2-phenylethyl)-9-isopropyl-9H-purine-2,6-diamine
  • N 2 (4 ⁇ fluorobenzyl)-9-isopropyl-9H-purine-2,6-diamine
  • This compound (0.5g, 1.68mmoles) was dissolved in DMF (5mL) and added to a previously formed mixture of pyrazole (0.34g, 5mmoles) and 60%w/w NaH dispersion in DMF (lOmL). The reaction mixture was allowed to stir at 80°C for 18 hours. The solvent was evaporated under reduced pressure, and the crude material was dissolved in 50mL dichloromethane and washed with water (2X20mL).
  • N 2 [2-(2,5-dimethoxyphenyl)ethyl)-9-propyl-8-(pyrazol- 1 -yl)- 9H-purine-2,6-diamine; , N 2 [2r(2,4-dichlorophenyl)ethyl)-9-propyl-8-(pyrazol-l-yl)- 9H-purine-2,6-diamine; N 2 [2-(2-methoxyphenyl)ethyl)-9-propyl-8-(pyrazol-l-yl)- 9H-purine-2,6-diamine; N 2 2-phenylethyl-N 6 -isobutyl-9-propyl-8-(pyrazol- 1 -yl)- 9H-purine-2,6-diamine; N 2 (2-hydroxymethyl)benzyl-9-propyl-8-(pyrazol- 1 -yl)- 9H-purine-2,6-diamine; N 2 (4-
  • N benzyl-8-(3-phenyl-4-fluoropyrazol-l-yl)-9-ethyl-9H-purine-2,6-diamine N 2 benzyl-8-[3-(pyrid- 1 -yl)pyrazol- 1 -yl)-9-ethyl-9H-purine-2,6-diamine, N 2 benzyl-8-(pyrazol- 1 -yl)-9-isobutyl-9H-purine-2,6-diamine), N benzyl-8-(pyrazol- 1 -yl)-9-(2-fluoropropyl)-9H-purine-2,6-diamine), N 2 benzyl-8-(pyrazol-l-yl)-9-(n-pentyl)-9H-purine-2,6-diamine), N 2 benzyl-8-(pyrazol- 1 -yl)-9-(n-decyl)-9H-purine-2,
  • N 2 (2-phenylethyl)-8-(pyrazol- 1 -yl)-9-isopropyl-9H-purine-2,6-diamine), N 2 (4-fluorobenzyl)-8-(pyrazol- 1 -yl)-9-isopropyl-9H-purine-2,6-diamine), N 2 (2-naphyth- 1 -ylethyl)-8-(pyrazol- 1 -yl)-9-isobutyl-9H-purine-2,6-diamine), N 2 pyrid-4-yl-8-(pyrazol- 1 -yl)-9-isobutyl-9H-purine-2,6-diamine), N 2 benzothiazol-2-yl-8-(pyrazol- 1 -yl)-9-isobutyl-9H-purine-2,6-diamine), N 2 pyrimidin-2-yl-8-(pyrazol-l-yl)-9-isobuty
  • N 2 benzyl-8-(4-iodopyrazol-l-yl)-9-ethyl-9H-purine- 2,6-diamine 50mg, O.lmmoles
  • p-tolyl boronic acid 30mg, 0.2mmoles, pre-dissolved in 0.2mL of ethanol
  • 2M aqueous sodium carbonate solution Nitrogen was bubbled through before and after adding Pd(PPh3)4 (4mg) and the reaction mixture was stirred at reflux for 24 hours.
  • the excess boronic acid was quenched by the addition of 30% hydrogen peroxide, and dichloromethane added.
  • R is Benzyl
  • R , R , R are Hydrogen
  • X is -NH-
  • N 2 (2-phenylethyl)-N 6 -(2,2-dimethylpropionyl) 8-(pyrazol- 1 -yl)-9-isopropyl-9H-purine-2,6- diamine
  • N 2 (4-fluorobenzyl)-N 6 -(2,2-dimethylpropionyl) 8-(pyrazol-l-yl)-9-isopropyl-9H-purine-2,6- diamine
  • the above ingredients are mixed and filled into hard gelatin capsules.
  • a tablet formula is prepared using the ingredients below: Quantity
  • the components are blended and compressed to form tablets.
  • EXAMPLE 12 A dry powder inhaler formulation is prepared containing the following components: Ingredient Weight %
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50 °C to 60 °C and passed tlirough a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • EXAMPLE 14 Suppositories, each containing 25 mg of active ingredient are made as follows:
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • a subcutaneous formulation may be prepared as follows: ingredient Quantity
  • EXAMPLE 17 An injectable preparation is prepared having the following composition:
  • a topical preparation is prepared having the following composition: Ingredients grams
  • the sustained release formulations of this invention are prepared as follows: compound and pH-dependent binder and any optional excipients are intimately mixed(dry-blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base which is sprayed into the blended powder. The granulate is dried, screened, mixed with optional lubricants (such as talc or magnesium stearate), and compressed into tablets.
  • Preferred aqueous solutions of strong bases are solutions of alkali metal hydroxides, such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of water-miscible solvents such as lower alcohols).
  • the resulting tablets may be coated with an optional film-forming agent, for identification, taste-masking purposes and to improve ease of swallowing.
  • the film forming agent will typically be present in an amount ranging from between 2% and 4% of the tablet weight.
  • Suitable film-forming agents are well known to the art and include hydroxypropyl. methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/ methyl-butyl methacrylate copolymers - Eudragit® E - Rohm. Pharma), and the like. These film-forming agents may optionally contain colorants, plasticizers, and other supplemental ingredients.
  • the compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression.
  • the tablet size will depend primarily upon the amount of compound in the tablet.
  • the tablets will include from 300 to 1100 mg of compound free base.
  • the tablets will include amounts of compound free base ranging from 400-600 mg, 650-850 mg, and 900-1100 mg.
  • the time during which the compound containing powder is wet mixed is controlled.
  • the total powder mix time i.e. the time during which the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes and preferably from 2 to 5 minutes.
  • the particles are removed from the granulator and placed in a fluid bed dryer for drying at about 60°C.
  • EXAMPLE 20 A2B adenosine receptor assays Methods Radioligand binding. Human A 2B adenosine receptor cDNA was stably transfected into
  • Hek-293 cells Monolayer of Hek-A2B cells were washed with PBS once and harvested in a buffer containing 10 mM HEPES (pH7.4), 10 mM EDTA and protease inhibitors. These cells were homogenized in polytron for 1 minute at setting 4 and centrifuged at 29000 g for 15 minutes at 4°C. The cell pellets were washed once with a buffer containing 10 mM HEPES (pH7.4), 1 mM EDTA and protease inhibitors, and were resuspended in the same buffer supplemented with 10% sucrose. Frozen aliquots were kept at -80°C.
  • Competition assays were started by mixing 10 nM 3H-ZM214385 (Tocris Cookson) with various concentrations of test compounds and 25 ug membrane proteins in TE buffer (50 mM Tris and 1 mM EDTA) supplemented with 1 U/ml adenosine deaminase. The assays were incubated for 90 minutes, stopped by filtration using Packard Harvester and washed four times with ice-cold TM buffer (10 mM Tris, 1 mM MgC12, pH 7.4). Non specific binding was determined in the presence of 10 uM ZM214385. B max and K D values were calculated using GraphPad software. cAMP measurements.
  • Monolayer of Hek-A2B cells were collected in PBS containing 5 mM EDTA. Cells were washed once with DMEM and resuspended in DMEM containing 1 U/ml adenosine deaminase at a density of 300,000 cells/ml. 100 ul of the cell suspension was mixed with 25 ul test compounds and the reaction was kept at 37°C for 10 minutes. At the end of 10 minutes, 125 ul 0.2N HCl was added to stop the reaction. Cells were centrifuged for 10 minutes at 1000 rpm. 100 ul of the supernatant was removed and acetylated. The concentration of cAMP in the supernatants was measured using the direct cAMP assay from Assay Design.
  • the compounds of Formula I were shown to be A 2 ⁇ -antagonists by the above tests.
  • EXAMPLE 21 A2B adenosine receptor assays
  • the human A 2B receptor cDNA is subcloned into the expression plasmid pDoubleTrouble as described in Robeva, A. et al, Biochem-Pharmacol., 51, 545-555 (1996).
  • the plasmid is amplified in competent JM109 cells and plasmid DNA isolated using Wizard Megaprep columns (Promega Corporation, Madison, WI).
  • a 2B adenosine receptors are introduced into HEK-293 cells by means of Lipofectin as described in Feigner, P. L. et al, Proc- Natl Acarl Sci- TJSA. 84. 7413-7417 (1987).
  • Transfected HEK cells are grown under 5% C0 2 /95% O 2 humidified atmosphere at a temperature of 37°C. Colonies are selected by growth of cells in 0.6 mg/mL G418. Transfected cells are maintained in DMEM supplemented with Hams F12 nutrient mixture (1/1), 10% newborn calf serum, 2 mM glutamine and containing 50 lU/mL penicillin, 50 mg/mL streptomycin, and 0.2 mg/mL Geneticin (G418, Boehringer Mannheim). Cells are cultured in 10 cm diameter round plates and subcultured when grown confluent (approximately after 72 hours). Radioligand binding studies.
  • Confluent mono layers of HEK-A 2B cells are washed with PBS followed by ice cold Buffer A (10 mM HEPES, 10 mM EDTA, pH 7.4) with protease inhibitors (10 ⁇ g/mL benzamidine, 100 ⁇ phenylmethanesulfonyl fluoride, and 2 g/mL of each aprotinin, pepstatin and leupeptin).
  • the cells are homogenized in a Polytron (Brinkmann) for 20 seconds, centrifuged at 30,000 x g, and the pellets washed twice with buffer HE (10 mM HEPES, 1 mM EDTA, pH 7.4 with protease inhibitors).
  • the final pellet is resuspended in buffer HE, supplemented with 10% sucrose and frozen in aliquots at -80°C.
  • membranes are thawed and diluted 5-10 fold with HE to a final protein concentration of approximately 1 mg/mL.
  • bovine serum albumin standards are dissolved in 0.2% NaOH/0.01 % SDS and protein determined using fluorescamine fluorescence. Stowell, C. P. et al, Anal. Biochem., 85., 572- 580 (1978).
  • H-ZM214385 tritiated 4-(2-[7-amino-2-(2furyl)[l,2,4]- triazolo[2,33-a][l,3,5]triazin-5- ylamino]ethyl) ⁇ henol) (17 Ci/mmol, Tocris Cookson, Bristol UK) (Ji, X. et al, Drug Design Discov.. 16, 216-226 (1999)), an adenosine A2 antagonist, displaced by the A 2B antagonists.
  • membranes 25 ⁇ g are resuspended in TE buffer (50 mM Tris and 1 mM EDTA) supplemented with 1 U/ml adenosine deaminase and mixed with 10 nM H- ZM214385 with or without various concentrations of test compounds .
  • the assay mixture is incubated for 90 minutes and then the reaction stopped by filtration through a Packard Harvester.
  • the filters are washed four times with ice-cold TM buffer (10 mM Tris, 1 mM MgCl 2 , pH 7.4).
  • Non specific binding is determined in the presence of 10 uM ZM214385.
  • the effect of the A 2B antagonists on the binding of the 125I" -ZM214385 to the membranes is determined by counting the radioactivity in a scintillation counter.
  • the Bmax and K D values are calculated using GraphPad software.
  • All non-radioactive compounds are initially dissolved in DMSO, and diluted with buffer to the final concentration, where the amount of DMSO never exceeds 2%. Incubations are terminated by rapid filtration over Whatman GF/B filters, using a Brandell cell harvester (Brandell, Gaithersburg, MD). The tubes are rinsed three times with 3 mL buffer each.
  • At least six different concentrations of competitor spanning 3 orders of magnitude adjusted appropriately for the IC 50 of each compound, are used.
  • IC 50 values calculated with the nonlinear regression method implemented in (Graph- Pad Prism, San Diego, CA), are converted to apparent ⁇ values as described. Linden, J., J. Cycl Nucl. Res., ,8.:163-172 (1982). Hill coefficients of the tested compounds are in the range of 0.8 to 1.1.
  • Cyclic AMP generation is performed in DMEM/HEPES buffer (DMEM containing 50 mM HEPES, pH 7.4, 37°C). Each well of cells is washed twice with DMEM/HEPES buffer, and then 100 ⁇ L adenosine deaminase (final concentration 10 IU/mL) and 100 ⁇ L of solutions of N-ethylcarboxyamido-adenosine (NECA), an adenosine receptor agonist, which stimulates cAMP synthesis, is added. Then, 50 ⁇ L of the test compound (appropriate concentration) or buffer are added to some of the wells.
  • DMEM/HEPES buffer DMEM containing 50 mM HEPES, pH 7.4, 37°C.
  • the cells After a 10 minute incubation at 37°C in an atmosphere of 5% CO 2 in air the cells are harvested and centrifuged for 10 minutes at 1000 rpm. 100 ⁇ l of the supernatant is removed and acetylated. The effect of the A 2B antagonist on the NECA-stimulation of cAMP is measured using the direct cAMP assay from Assay Design.

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Abstract

L'invention concerne de nouveaux composés représentés par la formule (I), antagonistes du récepteur de l'adénosine A2B, et utilisés pour traiter différents états maladifs notamment l'asthme et la diarrhée.
PCT/US2002/020631 2001-06-29 2002-06-27 Derives puriniques utilises comme antagonistes du recepteur de l'adenosine a2b WO2003002566A1 (fr)

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SI200230236T SI1401837T1 (sl) 2001-06-29 2002-06-27 Purinski derivati kot antagonisti adenozinskega receptorja A2B
EP02749704A EP1401837B1 (fr) 2001-06-29 2002-06-27 Derives puriniques utilises comme antagonistes du recepteur de l'adenosine a2b
DE60206756T DE60206756T2 (de) 2001-06-29 2002-06-27 Purin derivate als a2b adenosin rezeptor antagonisten
CA2451244A CA2451244C (fr) 2001-06-29 2002-06-27 Derives puriniques utilises comme antagonistes du recepteur de l'adenosine a2b
JP2003508947A JP4335000B2 (ja) 2001-06-29 2002-06-27 Ａ２ｂアデノシン・レセプタ拮抗剤
AT02749704T ATE307132T1 (de) 2001-06-29 2002-06-27 Purin derivate als a2b adenosin rezeptor antagonisten
KR1020037017083A KR100883292B1 (ko) 2001-06-29 2002-06-27 Ａ２ｂ 아데노신 수용체 길항제로서의 퓨린 유도체
HK04106852A HK1064096A1 (en) 2001-06-29 2004-09-09 Purine derivatives as a2b adenosine receptor antagonists.

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WO2005009445A1 (fr) * 2003-07-22 2005-02-03 Cv Therapeutics, Inc. Antagonistes du recepteur de l'adenosine a1
WO2005058898A2 (fr) * 2003-12-16 2005-06-30 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiesterase
JP2006515316A (ja) * 2003-05-06 2006-05-25 シーブイ・セラピューティクス・インコーポレイテッド Ａ２ｂアデノシンレセプターアンタゴニストであるキサンチン誘導体
WO2007030438A2 (fr) * 2005-09-06 2007-03-15 Pharmacopeia, Inc. Derives d'aminopurine permettant de traiter maladies neurodegeneratives
WO2007039297A1 (fr) * 2005-10-06 2007-04-12 Laboratorios Almirall, S.A. Dérivés d'imidazopyridine en tant qu'antagonistes du récepteur a2b de l'adénosine
WO2009118759A2 (fr) 2008-03-26 2009-10-01 Advinus Therapeutics Pvt. Ltd., Composés hétérocycliques utiles comme antagonistes des récepteurs adénosiniques
US7790728B2 (en) 2005-07-29 2010-09-07 Laboratorios Almirall, S.A. Pyrazine derivatives useful as adenosine receptor antagonists
WO2010103547A2 (fr) 2009-03-13 2010-09-16 Advinus Therapeutics Private Limited Composés de pyrimidine fusionnée substituée
WO2011055391A1 (fr) 2009-11-09 2011-05-12 Advinus Therapeutics Private Limited Composés pyrimidine fusionnés substitués, leur préparation et leurs utilisations
US7977477B2 (en) 2003-07-03 2011-07-12 Astex Therapeutics, Limited Benzimidazole derivatives and their use as protein kinase inhibitors
WO2012003220A1 (fr) 2010-06-30 2012-01-05 Gilead Sciences, Inc. Utilisation d'antagonistes de récepteur d'adénosine a2b pour traiter l'hypertension pulmonaire
US8110573B2 (en) 2004-12-30 2012-02-07 Astex Therapeutics Limited Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases
WO2012035548A1 (fr) 2010-09-13 2012-03-22 Advinus Therapeutics Private Limited Composés purine utilisés en tant que promédicaments des antagonistes du récepteur a2b de l'adénosine, leur procédé de préparation et leurs applications médicales
WO2012120082A1 (fr) 2011-03-08 2012-09-13 AristoCon GmbH & Co. KG Adénosine et ses dérivés à utiliser dans le traitement de la douleur
WO2012154340A1 (fr) 2011-04-07 2012-11-15 Gilead Sciences, Inc. Utilisation d'antagonistes de récepteur d'adénosine a2b pour traiter l'insuffisance cardiaque et l'arythmie chez des patients post-infarctus du myocarde
US8399442B2 (en) 2005-12-30 2013-03-19 Astex Therapeutics Limited Pharmaceutical compounds
US8435970B2 (en) 2006-06-29 2013-05-07 Astex Therapeutics Limited Pharmaceutical combinations of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea
TWI473809B (zh) * 2009-03-20 2015-02-21 Sigma Tau Ind Farmaceuti 可作為腺苷ａａ受體之配位子的三唑基嘌呤氧化衍生物以及彼作為藥物上的應用
US10703755B2 (en) 2016-04-26 2020-07-07 Sumitomo Dainippon Pharma Co., Ltd. Substituted purine derivative

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WO2003051882A1 (fr) * 2001-12-18 2003-06-26 Cv Therapeutics, Inc. Antagonistes du récepteur a2a de l'adénosine
NL1023355C2 (nl) * 2003-05-07 2004-11-09 Oce Tech Bv Hot melt inkt omvattend een mengsel van kleurstoffen.
WO2005047268A2 (fr) * 2003-11-10 2005-05-26 X-Ceptor Therapeutics, Inc. Compositions de pyrimidine substituee et procedes d'utilisation associes
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AU2007257423B8 (en) * 2006-05-31 2012-02-16 The Regents Of The University Of California Purine analogs
US7470697B2 (en) * 2006-09-01 2008-12-30 Adenosine Therapeutics, Llc Pyrrolo[3,2-D] pyrimidines that are selective antagonists of A2B adenosine receptors
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EP2200615A1 (fr) * 2007-10-16 2010-06-30 Gilead Palo Alto, Inc. Antagonistes du récepteur a3 de l'adénosine
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CA3131620A1 (fr) * 2019-03-05 2020-09-10 F-star Therapeutics, Inc. Composes, compositions et procedes pour le traitement d'une maladie
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ITRM20010465A1 (it) * 2001-07-31 2003-01-31 Sigma Tau Ind Farmaceuti Derivati della triazolil-imidazopiridina e delle triazolilpurine utili come ligandi del recettore a2a dell'adenosina e loro uso come medicam
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WO2000073307A2 (fr) * 1999-06-01 2000-12-07 University Of Virginia Patent Foundation 8-phenylxanthines substituees utiles comme antagonistes de recepteurs de l'adenosine a¿2b?
WO2001016134A1 (fr) * 1999-08-31 2001-03-08 Vanderbilt University Antagonistes selectifs des recepteurs a2b de l'adenosine

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JP2006515316A (ja) * 2003-05-06 2006-05-25 シーブイ・セラピューティクス・インコーポレイテッド Ａ２ｂアデノシンレセプターアンタゴニストであるキサンチン誘導体
US7977477B2 (en) 2003-07-03 2011-07-12 Astex Therapeutics, Limited Benzimidazole derivatives and their use as protein kinase inhibitors
JP2006528199A (ja) * 2003-07-22 2006-12-14 シーブイ・セラピューティクス・インコーポレイテッド Ａ１アデノシン受容体拮抗薬
WO2005009445A1 (fr) * 2003-07-22 2005-02-03 Cv Therapeutics, Inc. Antagonistes du recepteur de l'adenosine a1
WO2005058898A2 (fr) * 2003-12-16 2005-06-30 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiesterase
WO2005058898A3 (fr) * 2003-12-16 2005-08-11 Ranbaxy Lab Ltd Inhibiteurs de la phosphodiesterase
US8778936B2 (en) 2004-12-30 2014-07-15 Astex Therapeutics Limited Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases
US8110573B2 (en) 2004-12-30 2012-02-07 Astex Therapeutics Limited Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases
US7790728B2 (en) 2005-07-29 2010-09-07 Laboratorios Almirall, S.A. Pyrazine derivatives useful as adenosine receptor antagonists
WO2007030438A3 (fr) * 2005-09-06 2007-05-31 Pharmacopeia Drug Discovery Derives d'aminopurine permettant de traiter maladies neurodegeneratives
WO2007030438A2 (fr) * 2005-09-06 2007-03-15 Pharmacopeia, Inc. Derives d'aminopurine permettant de traiter maladies neurodegeneratives
ES2274712B1 (es) * 2005-10-06 2008-03-01 Laboratorios Almirall S.A. Nuevos derivados imidazopiridina.
US7855202B2 (en) 2005-10-06 2010-12-21 Laboratorios Almirall, S.A. Imidazopyridine derivatives as A2B adenosine receptor antagonists
ES2274712A1 (es) * 2005-10-06 2007-05-16 Laboratorios Almirall S.A. Nuevos derivados imidazopiridina.
WO2007039297A1 (fr) * 2005-10-06 2007-04-12 Laboratorios Almirall, S.A. Dérivés d'imidazopyridine en tant qu'antagonistes du récepteur a2b de l'adénosine
US8399442B2 (en) 2005-12-30 2013-03-19 Astex Therapeutics Limited Pharmaceutical compounds
US8435970B2 (en) 2006-06-29 2013-05-07 Astex Therapeutics Limited Pharmaceutical combinations of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea
WO2009118759A2 (fr) 2008-03-26 2009-10-01 Advinus Therapeutics Pvt. Ltd., Composés hétérocycliques utiles comme antagonistes des récepteurs adénosiniques
WO2010103547A2 (fr) 2009-03-13 2010-09-16 Advinus Therapeutics Private Limited Composés de pyrimidine fusionnée substituée
US9284316B2 (en) 2009-03-13 2016-03-15 Advinus Therapeutics Private Limited Substituted fused pyrimidine compounds
US8859566B2 (en) 2009-03-13 2014-10-14 Advinus Therapeutics Private Limited Substituted fused pyrimidine compounds
TWI473809B (zh) * 2009-03-20 2015-02-21 Sigma Tau Ind Farmaceuti 可作為腺苷ａａ受體之配位子的三唑基嘌呤氧化衍生物以及彼作為藥物上的應用
US8796290B2 (en) 2009-11-09 2014-08-05 Advinus Therapeutics Limited Substituted fused pyrimidine compounds, its preparation and uses thereof
WO2011055391A1 (fr) 2009-11-09 2011-05-12 Advinus Therapeutics Private Limited Composés pyrimidine fusionnés substitués, leur préparation et leurs utilisations
WO2012003220A1 (fr) 2010-06-30 2012-01-05 Gilead Sciences, Inc. Utilisation d'antagonistes de récepteur d'adénosine a2b pour traiter l'hypertension pulmonaire
WO2012035548A1 (fr) 2010-09-13 2012-03-22 Advinus Therapeutics Private Limited Composés purine utilisés en tant que promédicaments des antagonistes du récepteur a2b de l'adénosine, leur procédé de préparation et leurs applications médicales
US8940751B2 (en) 2010-09-13 2015-01-27 Advinus Therapeutics Private Limited Purine compounds as prodrugs of A2B adenosine receptor antagonists, their process and medicinal applications
DE102011005232A1 (de) 2011-03-08 2012-09-13 AristoCon GmbH & Co. KG Adenosin und seine Derivate zur Verwendung in der Schmerztherapie
WO2012120082A1 (fr) 2011-03-08 2012-09-13 AristoCon GmbH & Co. KG Adénosine et ses dérivés à utiliser dans le traitement de la douleur
WO2012154340A1 (fr) 2011-04-07 2012-11-15 Gilead Sciences, Inc. Utilisation d'antagonistes de récepteur d'adénosine a2b pour traiter l'insuffisance cardiaque et l'arythmie chez des patients post-infarctus du myocarde
EP3103454A1 (fr) 2011-04-07 2016-12-14 Gilead Sciences, Inc. Utilisation d'antagonistes du récepteur d'adénosine a2b pour le traitement de l'insuffisance cardiaque et de l'arythmie chez des patients post-infarctus du myocarde
US10703755B2 (en) 2016-04-26 2020-07-07 Sumitomo Dainippon Pharma Co., Ltd. Substituted purine derivative

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US20030064999A1 (en) 2003-04-03
KR100897219B1 (ko) 2009-05-14
US6770651B2 (en) 2004-08-03
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US7238700B2 (en) 2007-07-03
KR20040023634A (ko) 2004-03-18
KR100883292B1 (ko) 2009-02-11
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US20040209899A1 (en) 2004-10-21

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